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free radicals

In aging and many disease states, the energy
production capacity of the body’s cells is diminished.
The mitochondria are the structures within the cell
responsible for generating energy from oxygen and
nutrients. If their number is reduced or their function
is impaired, free radicals are produced and damaging toxins
accumulate in the cells. These toxins further damage the
mitochondria and impair other aspects of cellular function.
Many of the most common health problems, such as obesity,
diabetes, and many problems associated with aging, arise
from problems in cellular energy production. As one group of
researchers has put this, "[a]ging is associated with an overall
loss of function at the level of the whole organism that has
origins in cellular deterioration. Most cellular components,
including mitochondria, require continuous recycling
and regeneration throughout the lifespan."1 Another has
observed, "[m]itochondrial biogenesis [the creation of new
mitochondria] is a key physiological process that is required
for normal growth and development and for maintenance
of ongoing cellular energy requirements during aging."2
These observations link two key aspects of mitochondrial
health, preventing and removing damaged mitochondria
(mitophagy) and creating new mitochondria (mitogenesis).

Although the importance of the mitochondria as a
central point of health has been accepted for decades, over
the last few years the understanding of the mechanisms
involved has changed significantly. Twenty or ten years ago,
antioxidants and the free radical theory of aging largely
dominated thinking. Today, the importance of mitochondrial
biology linking basic aspects of aging and the pathogenesis
of age-related diseases remains strong, yet the emphasis has
changed. The focus has moved to mitochondrial biogenesis
and turnover, energy sensing, apoptosis, senescence, and
calcium dynamics.3

What Promotes Mitochondrial Biogenesis?
The body maintains a complex network of sensors and
signaling functions to maintain stability despite a constantly
changing environment and numerous challenges. Of special
note is the concept of hormesis, meaning a state in which
mild stress leads to compensation that improves the ability
of the body to respond in the future to similar challenges. It
turns out that many of the approaches that are associated
with longevity and healthy aging promote hormesis. In terms of mitochondria biogenesis, these include caloric restriction,
certain nutrient restrictions or shortages, caloric restriction
mimetics, and exercise.

Many of the mechanisms that activate mitochondrial
biogenesis in the face of hormesis have been elucidated.
Keeping in mind that there always must be a balance between
the elimination of worn-out and defective mitochondria and
the generation of new ones, the activators of both actions can
overlap. For instance, low energy levels (caloric restriction)
and increased reactive oxygen species/free radicals can
promote the activity of special cellular control points. These
include activating metabolic sensors such as AMP kinase/
AMPK (adenosine monophosphate kinase) and the protein
known as SIRT1 (sirtuin 1, i.e., silent mating type information
regulation 2 homolog 1). Activated AMPK is an indicator that
cellular energy is low and serves as a trigger to increase
energy production. It inhibits insulin/IGF-1/mTOR signaling,
all of which are anabolic and can lead not just to tissue
production, such as muscle growth, but also to fat storage.
Along with SIRT1, AMPK activates the biogenesis of new
mitochondria to enable the cell to generate more energy. At
the same time, activated AMPK and SIRT1 increase the activity
of a tumor suppressor that induces mitophagy. The balance
of the dual activations replaces defective mitochondria with
newly formed functionally competent mitochondria.

A key to health and healthy aging is to regulate the
catabolic processes via controlled amounts and
types of stressors such that worn out mitochondria
are removed without overshooting the mark and reducing
overall cellular and tissue functionality. The most successful
way to maintain this balance is to follow the body’s own
natural metabolic signals rather than to attempt to override
the body’s checkpoints. AMPK and SIRT1 ultimately are
energy/nutrient sensors or control points. Hence rather than
attempting to manipulate these directly, it likely is safer and
ultimately more effective to address the factors in the cell
that these sensors sense. The recent attention in the issue of
aging to the role of NAD+ (the oxidized form of nicotinamide
adenine dinucleotide) is a good example of this principle.
Directions coming from the nucleus of the cell that help
to regulate the normal production of NAD+ and the ratio
between distinct pools found in the cytoplasm and in the
mitochondria decline with age. The changes in the NAD+
from the nucleus lead to a disruption on the mitochondrial
side. In terms of energy production, it is a bit like losing a link
or two in the timing chain on your car engine with a resultant
reduction in engine efficiency. To date, attempts to increase
NAD+ in cells via supplementation with precursors have
not proven particularly successful. Major benefits have been
demonstrated in animal models only in the already seriously
metabolically impaired or the relatively old. Recent research
on oral supplementation has led to at least one extremely
difficult article which, at least in this author’s opinion, delivers
more smoke than heat.4,5 There is, however, an argument to
the effect that supplementing together both nicotinamide
riboside (a NAD+ precursor) and a sirtuin activator, such as
pterostilbene, may prove to be more successful.

It turns out that there are key points in normal cellular
energy generation processes that strongly influence the
NAD+ pools available for the cell to draw upon and the rate at
which NAD+ can be replaced in these pools. Aging has been
shown to promote the decline of nuclear and mitochondrial
NAD+ levels and to increase the risk of cancer along with
components of the metabolic syndrome. It is significant
that the risks of these conditions can be reduced in tandem.
Three places to start are 1) the pyruvate dehydrogenase
complex, 2) the tricarboxylic acid cycle (TCA cycle) also
known as the Krebs Cycle, and 3) the malate shuttle. A fourth
junction is Complex I of the electron transport system, again,
in the mitochondria.6 Manipulation of steps (1) and (2)
already is being used in cancer treatment.7 Readily available
dietary supplements can influence all four of these metabolic
bottlenecks.

Supplements for Promoting Mitochondrial Biogenesis
Medicine has started to pay a great deal of attention to
effecting mitochondrial biogenesis through not just drugs,
but also dietary supplements. Those interested should
go online and look up "Mitochondrial Biogenesis:
Pharmacological Approaches" in Current Pharmaceutical
Design, 2014, Vol. 20, No. 35. Quite a few options are
mentioned, including well known compounds, such as
R-lipoic acid (including with L-carnitine), quercetin and
resveratrol, along with still obscure supplements, including
various triterpenoids and the Indian herb Bacopa monnieri.

Pomegranate, French White Oak and Walnuts
The pomegranate, with its distinctive scarlet rind (pericarp)
and vibrantly colored seed cases (arils), is one of the oldest
cultivated fruits in the world. This exotic fruit features
prominently in religious texts and mythological tales and has
been revered through the ages for its medicinal properties.
An image of a pomegranate even can be found on the shield
of the British Royal College of Medicine. Numerous studies
have demonstrated the benefits of the fruit for cardiovascular
health with other benefits suggested in areas ranging from
arthritis to stability of cell replication to bone health. Now a
study in Nature Medicine (July 2016) has uncovered perhaps
the most important benefit of all, the ability of pomegranate
compounds (ellagitannins) transformed by gut bacteria to
protect the mitochondria of the muscles and perhaps other
tissues against the ravages of aging. The mitochondria are
the energy generators of the cells and the weakening of
this energy generating function in an increasing percentage
of mitochondria as we age is a primary source of physical
decline over the years. Urolithin A, a byproduct of gut
bacterial action on pomegranate compounds, allows the
body to recycle defective mitochondria and thereby slow or
even reverse for a time some of the major aspects of aging.
The lifespan in a nematode model of aging was increased by
more than 45 percent. Older mice in a rodent model of aging
exhibited 42 percent better exercise endurance. Younger
mice also realized several significant benefits.8

Beginning almost three decades ago, there were
numerous speculations in the research world regarding the
so-called "French Paradox" in which the French consumed
quite large amounts of saturated fat in the form of butter and cheese, yet consistently experienced much lower
rates of cardiovascular disease than did Americans. Not
only that, the French, especially in the southwest of the
country, typically led longer lives even in the areas noted for
consuming large amounts of goose fat and pate de foie gras,
which is to say, not just the Mediterranean diet based on
olive oil, etc. One hypothesis put forth very early on was that
it was the French consumption of red wine that protected
them. It was thought that red wine components, including
anthocyanidins, proanthocyanidins and resveratrol, are the
protective compounds. Not considered until recently is that
French red wines traditionally have been aged in casks made
from white oak (Quercus robur). White oak contains roburin
A, a dimeric ellagitannin related chemically to punicalagin.
Human data show relatively good absorption and conversion
of roburins into substances including urolithin A and ellagic
acid—as compared with ellagitannins in general, which
evidence only poor absorption. Hence, the benefits of good
red wine traditionally produced and good cognac (also aged
in oak barrels) involve urolithin A. Notably, the benefits of
roburins, most likely derived from the conversion to urolithin
A, go beyond mitophagy to include ribosomes, referring to cell
components that translate DNA instructions into specific
cellular proteins.9,10,11,12

Other sources of ellagitannins have been shown to lead
to the production of urolithin A by bacteria in the human
gut. Not surprisingly, sources of ellagitannins are foods
long associated with good health longevity, including not
just pomegranate and oak-aged red wine, but also walnuts
(and a smattering of other nuts), strawberries, raspberries,
blackberries, cloudberries and even black tea in small
amounts.

Exercise and Pyrroloquinoline Quinone (PQQ)
Peroxisome proliferator-activated receptor gamma coactivator
(PGC-1á) is the master regulator of mitochondrial
biogenesis.13 Exercise is perhaps the most significant
activator of PGC-1á that most individuals can access.
Exercise, furthermore promotes mitochondrial biogenesis
through a number of other pathways, especially endurance
and interval training.14

There are non-exercise options. You can’t take PGC-1á
orally because it is a large protein molecule which does not
survive digestion. PQQ is a small molecule that is available
when ingested and that increases circulating PGC-1á. PQQ
supplementation leads to more mitochondria and more
functional mitochondria.15

Fasting, Ketogenic Diets and Fasting-Mimicking Supplements
As already discussed, fasting promotes mitochondrial
biogenesis by AMPK activation.16 AMPK senses the energy
status of the cell and responds both to acute shortages,
such as that induced by exercise, and to chronic shortages,
such as from fasting. Probably due to an overall reduction
in metabolic rate, chronic caloric restriction (as opposed to
intermittent fasting) contributes to the health of mitochondria
rather than biogenesis.17 The robustness of AMPK response
decreases with age.18

Ketogenic diets (very low carbohydrate diets) also
promote increases in mitochondria.19 Few individuals are
willing or able to follow ketogenic diets chronically just as
few individuals are willing to undergo routine fasts. Fasting-mimicking
supplements offer an alternative approach. The
dietary supplement (-)–hydroxycitric acid (HCA) is the best
researched of these compounds. (Keep in mind that there
is a vast difference in the efficacy of commercially available
forms.20) Researchers have proposed that HCA used properly
can activate mitochondrial uncoupling proteins and related
effects.21

Furthermore, according to a study published in the journal
Free Radical Research in 2014, HCA improves antioxidant status
and mitochondrial function plus reduces inflammation in fat
cells.22 Inflammation is linked to the metabolic syndrome at
the cellular level by way of damage to the antioxidant enzyme
system (e.g., superoxide dismutase, glutathione peroxidase,
glutathione reductase) and mitochondria. This damage, in
turn, propagates further production of pro-inflammatory
mediators (e.g., TNF-á, MCP-1, IFN-ã, IL-10, IL-6, IL-1â).
HCA protected fat cells from ER stress by improving the
antioxidant status to reduce oxidative stress (i.e., reduce
ROS) and improve the function of the mitochondria to
short circuit an ER stress—inflammation loop in these cells.
Reducing TNF-á is important in that doing so removes a
major impediment to mitochondrial biogenesis.23

Other Supplements to Promote Mitochondrial Biogenesis

Scholarly reviews looking at natural compounds such as
those that are found in anti-aging diets suggest yet other
supplements to promote mitobiogenesis. For instance,
it turns out that hydroxytyrosol, the most potent and
abundant antioxidant polyphenol in olives and virgin olive
oil, is a potent activator of AMPK and an effective nutrient
for stimulating mitochondrial biogenesis and function via
what is known as the PGC-1á pathway.24 Another herb with anti-aging effect, this time by activating the malate shuttle
mechanism mentioned above, is rock lotus (Shi Lian Hua).
This herb has been described in detail in this magazine in
the article, "Uncovering the Longevity Secrets of the ROCK LOTUS."25

Conclusion
It is possible to improve the functional capacity of the
mitochondria through dietary practices, exercise and
supplements. Indeed, a number of compounds have been
identified by researchers as mitochondrial nutrients. These
compounds work together to increase the efficiency of energy
production, to reduce the generation of free radicals, and so
forth and so on. Likewise, these nutrients have been shown
to improve the age-associated decline of memory, improve
mitochondrial structure and function, inhibit the ageassociated
increase of oxidative damage, elevate the levels
of antioxidants, and restore the activity of key enzymes.
Perhaps best of all, the body can be encouraged both to
remove damaged mitochondria (mitophagy) and to create
new ones, which is to say, mitochondrial biogenesis.

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